The ovarian steroids are considered permissive or causal factors in the development of carcinomas in the breast and uterus in human females. These steroids are also known to stimulate proliferation of normal epithelial cells in these organs. Earlier studies by this and other laboratories suggested that the erbB family of receptor tyrosine kinases are important in mediating the proliferative action of estrogens during mammary gland morphogenesis. Direct analysis of these kinases in the gland support this notion. Tyrosine phosphorylation of epidermal growth factor receptor (EGFR or erbB-1) and erbB-2 occurred during mouse ductal morphogenesis and also when castrates were treated with estradiol or EGF. Waved-2 mice, which have impaired EGFR kinase activity (VaL 743 Gly), exhibited much less mammary development than that of wild-types when both were evaluated at 36 days of age. In addition, glands from EGFR null mutant mice failed to develop beyond rudimentary structures. These findings suggest that the EGFR is essential for estrogen-dependent morphogenesis of the mammary gland and functions as a hetero-dimer with erbB-2. Using similar experimental approaches we previously reported that estradiol stimulates the formation of a uterine complex consisting of the insulin-like growth factor-1 (IGF-1) receptor, the insulin receptor substrate-1 (IRS-1) docking protein and phosphoinositide 3-kinase. Other docking proteins are being analyzed as potential uterine IGF-1R substrates, such as the Grb-2 associated binder (GAB-1).